The bisphosphonates, which are salts of bisphosphonic acids, are an important class of medicaments useful in the treatment of bone disorders such as Paget's disease and osteoporosis.
The bisphosphonates, for example etidronate, pamidronate, and risedronate are used in the form of various non-toxic and pharmaceutically acceptable esters, alkali metal salts and salts of alkaline-earth metals and their various hydrates. The form of the substance can have a fundamental influence on its solubility and its biological availability. The preferred forms of risedronate are the sodium and calcium salts.
Risedronic acid, chemically known as [1-hydroxy-2(3-pyridinyl)ethylidene]bisphosphonic acid, presently marketed as risedronate sodium under the tradename Actonel, is an important active pharmaceutical ingredient for the treatment of osteoporosis.
Risedronic acid and its pharmaceutically acceptable salts were first disclosed in U.S. Pat. No. 5,583,122. U.S. Pat. No. 5,583,122 discloses risedronic acid, but its preparation is not exemplified. On the contrary, the patent discloses the synthesis of an isomer, 1-hydroxy-2-(2-pyridyl)-1,1-diphosphonic acid, by reaction of (2-pyridyl) acetic acid with phosphorous acid and phosphorus trichloride in chlorobenzene. At the end of the reaction, the mixture solidifies and the solvent is removed by decantation.
But as described, when the reaction is carried out in chlorobenzene as a diluent, it does not solubilize the reaction components. The reaction starts as a two phase system, in which the melt gradually thickens into a non-stirrable mass. This semisolid sticky mass finally turns into a hard, rigid material coated on the walls of the reaction vessel which is preventing smooth heat transfer. The process might be suitable for laboratory preparation of gram quantities of the product; however, for industrial production it is not acceptable and is not reasonable even for a modest scale up.
U.S. Pat. No. 5,908,959 teaches use of long chain glycols to attempt to prevent the solidification of the reaction mixture, however the solidification cannot be totally avoided and these glycols cannot be recycled as they get converted to their corresponding chloride derivatives, which could be potentially toxic.
U.S. Pat. No. 5,648,491 discloses the use of methanesulfonic acid as reaction solvent. However, this technique involves the risk of safety as this solvent gives rise to uncontrollable reactions in the reaction conditions, when the temperature of the reacting mixture exceeds 85° C. Also, methanesulfonic acid is corrosive to skin, irritant and quite expensive.
U.S. Pat. No. 6,562,974 discloses a process for the preparation of geminal bisphosphonate using pyridine hydrochloride, morpholine hydrochloride & phosphoric acid at 70° C.
US Patent application 2004/0043967A1 discloses a process for the preparation of risedronate comprising the use of aromatic hydrocarbon or a silicone fluid optionally with poly-alkene glycol. However, these solvents have a high cost and are difficult to eliminate from the finished product because of their high boiling point. Also, large quantities of poly-alkene glycol are required for the reaction, making it inefficient for use on a large scale.
PCT application WO 03/93282A1 describes a process for the preparation of risedronate & its monovalent cation using ionic liquid (tri-butyl ammonium chloride) as solvent at 15-120° C. The disclosed invention uses a solvent which is an expensive reagent, difficult to recover. Also, the yields reported are very low.
PCT application WO 05/044831A2 describes a process for the preparation of risedronic acid by using sulfolane as reaction solvent. Quenching of the reaction mixture containing sulfolane, with water causes high exothermicity and reaction becomes uncontrollable, hence is difficult to handle.
PCT application WO05/63779A2 describes a process for the preparation of risedronate using a mixture of phosphorous acid & phosphorous chloride in the absence of solvent. Requirement of more reaction time and large quantities of reactants for the reaction makes the process inefficient and expensive for use on a large scale. Also, the yields obtained are very low.
It is evident from prior art that different processes known for the preparation of risedronic acid and its pharmaceutically acceptable salts have some disadvantages associated with their use. So, there is an urgent need to develop a process for the preparation of risedronic acid or its salts that may overcome the drawbacks of prior art processes and should be industrially viable.
Accordingly, it is an object of the present invention to provide an efficient, safe and convenient process for preparation of risedronic acid wherein a water miscible neutral solvent such as acetonitrile is used and is further converted to risedronic acid monosodium salt in high yield and purity